ABSTRACT A major goal of stem cell research is to derive high-quality human pluripotent stem cells (hPSCs) that possess the unique transcriptional, epigenetic and functional properties of developmentally unrestricted ?nave? pluripotent cells found in the pre-implantation blastocyst in vivo. In contrast, hPSCs derived under traditional conditions represent a more advanced or ?primed? developmental state that corresponds to the late post-implantation epiblast. My work and that of others has shown that primed hPSCs can be repro- grammed into a nave state marked by expression of early embryonic transcription factors, globally re- duced DNA methylation levels and X chromosome reactivation in female cells. However, the widespread utilization of nave hPSCs in biomedical research is currently impaired by epigenetic instability during es- tablishment and maintenance of the nave state. In particular, nave hPSCs generated with currently avail- able methods display irreversible erasure of parent-specific imprinting and retain an epigenetic memory of the inactive X chromosome in female cells. Based on recent studies in mouse, and my preliminary data in human cells, I hypothesize that aberrant epigenetic reprogramming during induction of na- ve pluripotency is a consequence of inappropriate signal perturbation. I will employ reporter-based combinatorial chemical screening to capture nave hPSCs that faithfully recapitulate the epigenome of human pluripotent cells in vivo, and apply these insights to establish novel stem cell models of human disease. My specific goals are to preserve parent-specific imprinting during induction of nave pluripotency, enable random XCI upon differentiation in female cells, and assess the competence of epigenetically stable nave hPSCs for unbiased differentiation into all three germ layers. In addition, I propose to exploit the unique properties of nave hPSCs to investigate disease mechanisms that cannot be adequately modeled in conventional hPSCs, such as the epigenetic basis of early pregnancy loss and X-linked disorders. The overall aim of this project is to exploit the presently untapped biomedical potential of nave hPSCs and generate a robust cellular platform for disease modeling and regenerative medicine.